Synergistic Interaction Between Fentanyl and a Tramadol:Paracetamol Combination on the Inhibition of Nociception in Mice

Abstract

In clinics, the use of drug-drug combinations in order to manage acute and chronic pain is well established. On the one hand, analgesics are staggered according to pain severity: mild, moderate, and severe pain, and thus patients should progress through this analgesic ladder depending on the pain relief obtained. On the other hand, analgesic adjuvants should also be added in order to reach analgesia using lower doses of the drugs (i.e., opioids) used, thus reducing the incidence of adverse side-effects. However, although there is precise categorization of analgesics within drug-drug combinations, these multimodal analgesic approaches are most of the times based on empirical instead of accurate experimental data. In such a way, tramadol (TRM) and paracetamol (PRC) have been revealed as analgesic drugs that would synergically interact with opioid drugs (1, 2). Furthermore, the combination of TRM and PRC is also a common multimodal analgesic strategy that has been shown to be effective and generally well tolerated in patients with moderate to severe pain (3). Accordingly, in the present study we attempted to characterize the combination of the major opioid fentanyl (FEN) with a tramadol:paracetamol (TRM:PRC) mixture, in order to examine whether the analgesic effects of the mixture would be enhanced together with a FEN-dosage reduction and the consequent diminution of opioid-related adverse effects (i.e., constipation). In addition, we evaluated the role of opioid receptors in such drug-drug interaction, since both TRM and PRC possess diverse and complex mechanisms of action, in which the modulation of the opioid system would be included (4 -6).First of all, we analyzed the antinociceptive effects of the individual drugs. Briefly, male Swiss CD1 mice (20 -25 g) housed under controlled standard conditions (12-h dark/light cycle, 22°C temperature and 66% humidity) were injected with one or a mixture of the following drugs: FEN (KernPharma, Barcelona, Spain); TRM (Grünenthal, Madrid, Spain); PRC (Bristol-Myers Squibb, Madrid, Spain); naloxone (Sigma-Aldrich, St. Louis, MO, USA); naltrindole and nor-binaltorphimine (nor-BNI) (Tocris Bioscience, Bristol, UK) subcutaneously 30 min before testing. Then, mice were injected intraperitoneally with an acetic acid solution (0.6% v/v, 10 ml/kg) and placed in a clear plexiglass cylinder to observe after 5 min the number of writhes (a single writhe is defined as a contraction of the abdominal wall together with the twisting of the trunk and hind limbs extension) in a 5-min period (6). The Institutional Committee on Animal Use and Care, in accordance with the International Association for the Study of Pain guidelines on ethical standards for investigation in animals, approved the protocol. As previously described, FEN and PRC Barcelona, L'Hospitalet de Llobregat, 08907 Barcelona, Spain Received September 1, 2011; Accepted December 25, 2011 Abstract. Multimodal analgesic approaches to manage acute and chronic pain are commonly used in humans. Here, we attempted to characterize...

Participation of ATP‐sensitive K+ channels and μ‐opioid receptors in the antinociceptive synergism of the paracetamol–tapentadol co‐administration in the formalin‐induced pain assay in mice

“…All these findings were confirmed using both isobolographic analysis and interaction index. Similar results have been observed when other NSAIDs and tapentadol were used in somatic and visceral animal pain models (Barreras‐Espinoza et al, ; Zapata‐Morales et al, , ) as well as when paracetamol has been used in combination with other opioid analgesics in the formalin and acetic acid assays in rodents (Fernández‐Dueñas, Poveda, Sánchez, & Ciruela, ; Janovsky and Krsiak, ; Miranda, Puig, Dursteler, Prieto, & Pinardi, ; Miranda, Noriega, & Prieto, ).…”

Clinical Management of Pain in Rodents

“…150,152 Opioids also enhance the effects of tramadol. 59,175 In a murine laparotomy model, mice were treated with either buprenorphine alone or in combination with carprofen, administered in the drinking water. 164 The combination of buprenorphine and carprofen provided the best analgesia, compared with buprenorphine alone, and carprofen alone failed to provide any analgesia.…”

Effects of Multimodal Analgesic Protocol, with Buprenorphine and Meloxicam, on Mice Well-Being: A Dose Finding Study

“…Buprenorphine and indomethacin [ 8 ], buprenorphine and carprofen [ 5 , 28 ], morphine and various NSAIDs [ 29 ], and fentanyl and paracetamol [ 7 ] have been used in multimodal approaches in mice with a combination of opioids and NSAIDs. This is probably the first study to evaluate a multimodal approach using buprenorphine and meloxicam in mice [ 28 , 30 ].…”

“…The multimodal approach is not commonly used in postoperative pain management in rodents. While there are reports of positive effects for postoperative pain management [ 5 , 7 ], there are also reports of single analgesics being more effective [ 8 ], or having negative effects [ 9 ], and reports on their efficacy, adverse effects, and effects on animal well-being are not enough [ 2 ].…”